We have been studying a murine gammaherpesvirus, MHV68, that like human EBV is tropic for lymphocytes and establishes latency in B cells. Mice infected with the virus exhibit rapid activation of CD4 and CD8 T cells in lung, lymph node and spleen and virus-specific antibodies were detected by 12 days after infection. However, virus-specific cytotoxic T lymphocytes (CTL) were not detected after primary or secondary infections. Full resistance was shown to be require both CD4 and CD8 T cells and appeared to require expression of inducible nitric oxide synthase produced in response to interferon gamma. This virus may serve as a small animal model for acute and chronic infections of humans with EBV.